Extended release oral dosage composition

ABSTRACT

A bilayer solid composition comprising (a) an immediate release first layer comprising an anti-allergic effective amount of desloratadine and at least one pharmaceutically acceptable excipient and (b) a sustained release second layer comprising an effective amount of a nasal decongestant, e.g. pseudoephedrine sulfate and a pharmaceutically acceptable sustained release agent wherein the composition contains less than about 2% of desloratadine decomposition products is disclosed. A solid composition comprising an anti-allergic effective amount of desloratadine and at least one, and preferably two pharmaceutically acceptable antioxidants is also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/699,987, filed Nov. 3, 2003, which is a continuation applicationof U.S. application Ser. No. 10/175,480 filed Jun. 19, 2002, now grantedas U.S. Pat. No. 6,709,676 on Mar. 23, 2004, which is acontinuation-in-part of International Application No. PCT/US00/34404filed Dec. 19, 2000, from which priority is claimed pursuant to 35U.S.C. §365(c) and §120, which application claims the benefit of U.S.Provisional Application Ser. No. 60/172,752 filed Dec. 20, 1999 under 35U.S.C. §119(e).

BACKGROUND OF THE INVENTION

This invention relates to oral dosage compositions, including a bilayersustained release oral dosage composition containing a nasaldecongestant, e.g., pseudoephedrine in one layer and the non-sedatingantihistamine, desloratadine in a second layer and having less thanabout 2% of desloratadine degradation products in the compositions. Theoral dosage compositions of this invention are useful for treatingpatients showing the signs and symptoms associated with allergic and/orinflammatory conditions such as the common cold, as well as signs andsymptoms associated with allergic and/or inflammatory conditions of theskin such as dermatitis, and airway passages such as the upperrespiratory disease conditions, perennial allergic rhinitis, seasonalallergic rhinitis and nasal congestion, allergic asthma, and nasalcongestion.

Desloratadine, also called descarbethoxyloratadine, is disclosed in U.S.Pat. No. 4,659,716 as a non-sedating antihistamine useful as ananti-allergy agent. U.S. Pat. No. 5,595,997 discloses methods andcompositions for treating seasonal allergic rhinitis symptoms usingdesloratadine.

U.S. Pat. Nos. 4,990,535 and 5,100,675 disclose a twice-a-day sustainedrelease coated tablet wherein the tablet coating comprisesdescarbethoxyloratadine and a hydrophilic polymer and polyethyleneglycol, and the tablet core comprises acetaminophen, pseudoephedrine ora salt thereof, a swellable hydrophilic polymer and pharmaceuticallyacceptable excipients.

U.S. Pat. No. 5,314,697 discloses an extended release tablet containingmatrix core comprising pseudoephedrine sulfate and a coating comprisingloratadine.

None of the prior art discloses the solid oral dosage compositions ofthis invention.

The successful development of a formulation of adesloratadine-pseudoephedrine twice-a-day and once-a-day products wouldbe desirable, but would require (1) achieving a release rate profile forpseudoephedrine component over an extended period of about twelve hoursor twenty four hours, respectively, while maintaining the safety andeffectiveness of desloratadine, and (2) minimizing impurity formationdue to the interaction between desloratadine and excipients in thepseudoephedrine layer that are incompatible with desloratadine.

It would be desirable for increased patient compliance to have a stable,extended release desloratadine-pseudoephedrine product substantiallyfree of desloratadine impurities and additional polymorphic forms thatis effective and safe when used on a twice-a-day or once-a-day basis forthe treatment, management and/or mitigation of the signs and symptomsassociated with the common cold, as well as allergic and/or inflammatoryconditions of the skin or upper and lower airway passages such asseasonal and perennial allergic rhinitis and nasal congestion.

SUMMARY OF THE INVENTION

We have found that desloratadine discolors and decomposes in thepresence of excipients disclosed in the prior art. We have discoveredthat these problems are substantially solved by (a) bilayer solidcompositions of the present invention wherein immediate release layercontains desloratadine combined with a pharmaceutically acceptablecarrier medium comprising a desloratadine protective amount of apharmaceutically acceptable basic salt, and wherein the use of an acidicexcipient in the immediate release layer is substantially avoided or (b)bilayer solid compositions of the present invention wherein adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant is present in at least one layer, and preferably,wherein two of said antioxidants are present in desloratadine-containingimmediate release layer.

Thus, this invention provides a bilayer solid composition comprising (a)an immediate release first layer comprising an anti-allergic effectiveamount of desloratadine and at least one pharmaceutically acceptableexcipient and (b) a sustained release second layer comprising aneffective amount of a nasal decongestant and a pharmaceuticallyacceptable sustained release agent wherein the total amount ofdesloratadine decomposition products in the composition is less than, orequal to, about 2% by weight.

This invention also provides a bilayer solid composition comprising (1)an immediate release first layer comprising an anti-allergic effectiveamount of desloratadine and a desloratadine-protective amount of apharmaceutically acceptable water insoluble basic calcium, magnesium oraluminum salt, or of a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant; and (2) a sustained releasesecond layer comprising an effective amount of pseudoephedrine or a saltthereof, and a pharmaceutically acceptable sustained release agent, andoptionally a desloratadine-protective amount of a pharmaceuticallyacceptable antioxidant.

Thus, in one preferred embodiment, this invention provides a bilayersolid composition comprising (1) an immediate release first layercomprising an anti-allergic effective amount of desloratadine anddesloratadine-protective amount of a pharmaceutically acceptable waterinsoluble basic calcium, magnesium or aluminum salt, and (2) a sustainedrelease second layer comprising an effective amount of pseudoephedrineor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable sustained release agent. The immediate release layer issubstantially free of, i.e., contains less than about 1%, preferably,less than about 0.5%, and more preferably less than about 0.25% ofacidic excipients.

The total amount of desloratadine decomposition products in thepharmaceutical compositions of this invention is less than, or equal to,about 2.0%, and preferably is less than, or equal to, about 1.4% byweight when such compositions are stored at 25° C. and about 60%relative humidity for extended time periods, e.g., at least about 12 toabout 18 months.

In another preferred embodiment, this invention provides a bilayer solidcomposition comprising:

(a) an immediate release first layer comprising:

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn starch 11.0Dibasic calcium phosphate dihydrate 53.0 Microcrystalline cellulose30.22 Talc 3.0 FD&C Blue dye No. 2 Aluminium Lake 5627 0.28 TOTAL INFIRST LAYER 100.00and

(b) a second sustained release second layer comprising:

INGREDIENT mg/composition Pseudoephedrine Sulfate 120.0 HydroxypropylMethylcellulose 105.0 Microcrystalline cellulose 100.0 Povidone 18.0Silicon Dioxide 5.0 Magnesium stearate 2.0 TOTAL IN SECOND LAYER 350.0

The total amount of desloratadine decomposition products such asN-formyl-desloratadine (see Chart I) in the above-listed preferredbilayer compositions is less than about 2.0% by weight when suchcompositions are stored at 25° C. and about 60% relative humidity forextended time periods of at least about 15 to about 18 months.

In another preferred embodiment, the present invention also provides abilayer solid composition comprising (1) an immediate release firstlayer comprising an anti-allergic effective amount of desloratadine anda desloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant; and (2) a sustained release second layercomprising an effective amount of pseudoephedrine or a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable sustained releaseagent, and a desloratadine-protective amount of a pharmaceuticallyacceptable antioxidant. The total amount of desloratadine decompositionproducts such as N-formyldesloratadine (see Chart I) in the above-listedpreferred bilayer compositions is less than about 2.0% by weight whensuch compositions are stored at 25° C. and about 60% relative humidityfor extended time periods of at least about 15 to about 18 months.

This invention further provides in another preferred embodiment abilayer solid composition comprising (a) an immediate release firstlayer comprising an anti-allergic effective amount of desloratadine andat least one pharmaceutically acceptable excipient and (b) a sustainedrelease second layer comprising an effective amount of pseudoephedrineor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable sustained release agent and wherein the total amount ofdesloratadine decomposition products in the bilayer solid composition isless than about 2.0% by weight when such compositions are stored at 25°C. and about 60% relative humidity for extended time periods of at leastabout 15 to about 18 months.

In another preferred embodiment, the present invention also provides abilayer solid composition comprising (1) an immediate release firstlayer comprising 5 mg of desloratadine and desloratadine-protectiveamount of a pharmaceutically acceptable water insoluble basic calcium,magnesium or aluminum salt, and (2) a sustained release second layercomprising 120 mg of pseudoephedrine sulfate, and a pharmaceuticallyacceptable sustained release agent.

In another preferred embodiment, the present invention also provides abilayer solid composition comprising (1) a first layer comprising 2.5 mgof desloratadine and a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant; and (2) a second layercomprising 120 mg of pseudoephedrine or a pharmaceutically acceptablesalt thereof, a pharmaceutically acceptable excipient. Preferably thereare two pharmaceutically acceptable antioxidants in the first immediatelayer.

In another preferred embodiment, the present invention also provides abilayer solid composition comprising (1) a first layer comprising 5.0 mgof desloratadine and a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant; and (2) a second layercomprising 120 mg of pseudoephedrine or a pharmaceutically acceptablesalt thereof, a pharmaceutically acceptable excipient. Preferably thereare two pharmaceutically acceptable antioxidants in the first immediatelayer.

In another preferred embodiment, the present invention also provides asolid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid compositions.

In another preferred embodiment, the present invention also provides asolid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid composition.

We have also found that the total amount of desloratadine decompositionproducts in the 2.5 mg and 5.0 mg solid compositions is less than about2.0%, and at least about 80% of the desloratadine in the 2.5 mg and 5.0mg solid compositions of the present invention dissolves in 0.1N HCl at37° C. in about 45 minutes.

Thus, the present invention also provides a method of using the solidcompositions of the present invention for treating and/or preventingallergic and inflammatory conditions of the upper and lower airwaypassages and skin which comprises administering to a patient in need ofsuch treating an effective amount of a solid composition of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

During the course of development of the compositions of the presentinvention, desloratadine was found to be unstable and to discolor whenstored in combination with various excipients such as those disclosed inU.S. Pat. No. 5,314,697 as part of the matrix core containingpseudoephedrine sulfate. We have discovered two solutions to minimizeformation of desloratadine degradation products. In one embodiment, weincorporate a desloratadine protective amount of a pharmaceuticallyacceptable basic salt in the immediate release layer containingdesloratadine, and substantially avoid the use of an acidic excipient inthe immediate release layer. In the second embodiment, we incorporate adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant in at least one layer and preferably weincorporate two of said antioxidants into desloratadine-containingimmediate release layer.

In the bilayer solid compositions containing a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum salt, wefound that the excipients in the immediate release layer causingdiscoloration and instability of desloratadine include acidic excipientshaving a pH of less than 7 in water such as organic acids, such asstearic acid, povidone, crospovidone as well as the hydroxycarboxylicacid, ascorbic acid, and carbonyl-containing materials such as lactose,and ethylcellulose and hydroxylpropyl methylcellulose. In this preferredembodiment, we also discovered that it is possible to prepare a bilayertablet containing desloratadine in an immediate release first layer inintimate contact with a sustained release second layer containing anasal decongestant and excipients incompatible with desloratadine byincorporating a desloratadine protective amount of a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum saltinto the immediate release desloratadine layer, and substantiallyavoiding the use of, that is having less than about 0.1% by weight,prefabably less than about 0.5%, and more prefabably less than about0.25% of acidic excipients in the immediate release layer.

Binders like povidone and polymers such as hydroxypropyl methylcelluloseare useful as a polymer matrix for the sustained release of apharmaceutically acceptable pseudoephedrine salt, preferablypseudoephedrine sulfate, from the sustained release layer.

We also discovered that metal ions catalyzed were involved in theformation of desloratadine degradation products. In a preferredembodiment, a desloratadine-protective amount of a pharmaceuticallyacceptable anti-oxidant should be present in at least one of thebilayers, preferably one of said antioxidant is present in each layer,and more preferably two pharmaceutically acceptable anti-oxidants arepresent in the desloratadine layer.

The term “pharmaceutically acceptable antioxidant” as used herein inreference to desloratadine (“DL”, formula I in the Chart) means apharmaceutically acceptable chelating agent that protects desloratadinefrom the formation of degradation products including, but not limited tothose of the formulas II-VII listed in the Chart, e.g.,N-formyl-desloratadine or N-formyl DL (formula II in the Chart),N-hydroxylamine of DL (formula V in the Chart) N-oxide of DL (formula IVin the Chart), and the 3′-hydroxyl N-oxide of DL (formula III in theChart), N-methyl DL (formula VI in the Chart), and the ketone of formulaVII. The structures listed in the Chart were determined by standardphysiochemical techniques, e.g., LC-MS, and LC-NMR.

Typically suitable pharmaceutically acceptable antioxidants for DL arepharmaceutically acceptable chelating agents such as those disclosed in“Chelating Agents”, pages 764-794, Vol. 5 of KIRTH-OTHMER, ENCYCLOPEDIAOF CHEMICAL TECHNOLOGY, 4^(th) Edition, 1993, John Wiley & Sons Inc.,NY, and preferably including, but not limited to, hydroxycarboxylicacids, such as tartaric acid, citric acid and gluconic acid, andpharmaceutically acceptable salts thereof, aminocarboxylic acids such asiminodiacetic acid, N-methyliminodiacetic acid, nitrolotriacetic acid,edetic acid (ethylenediamine tetraacetic acid),diethylenetriaminepentaacetic acid, 1,2-diaminocyclohexanetetraaceticacid or N-hydroxylethylenediaminetriacetic acid, and pharmaceuticallyacceptable salts thereof such as the alkali and alkaline earth salts,e.g., edetate calcium disodium, edetate disodium, edetate trisodium, andedetate tetrasodium. Edetate disodium and citric acid are the preferredpharmaceutically acceptable antioxidants. Use of the hydroxycarboxylicacid, ascorbic acid, is to be avoided

The desloratadine protective amount of a pharmaceutically acceptableantioxidant in the desloratadine immediate release layer is in the rangeof about 0.1% to about 10% by weight, preferably about 1% to 8% or about1% to about 6%, more preferably about 3% to about 8%, or about 4% toabout 6%, or most preferably about 5%. In a preferred embodiment of thisinvention, two antioxidants are present in the immediate releasedesloratadine layer, one antioxidant, e.g., edeate disodium, in anamount of about 1% to about 8%, preferably about 3% to about 8%, morepreferably about 4% to about 6%, or most preferably about 5%, and thesecond antioxidant, e.g., citric acid, is present in an amount of about1% to about 8%, preferably about 3% to about 8%, more preferably about4% to about 6%, or most preferably about 5%. The pharmaceuticallyacceptable antioxidant in the pseudoephedrine sulfate (“PES”) sustainedrelease layer is in the range of 0% to about 10%, preferably about 0.1%to about 10%, or about 0.1% to about 3%, more preferably about 1 toabout 2%, and most more preferably about 1.0%. In a preferred embodimentof the present invention, about 1.0% by weight of a pharmaceuticallyacceptable antioxidant, e.g., edetate disodium, is present in the PESsustained release layer. In another preferred embodiment, about 6% byweight of a mixture of two pharmaceutically acceptable antioxidants,e.g., edetate disodium and citric acid, are present in the DL immediaterelease layer in a ratio of about 5:1 to about 1:5, preferably about5:1, and about 1% of a pharmaceutically acceptable antioxidant, e.g.,edetate disodium, is present in the sustained release layer. In anotherpreferred embodiment, about 5% by weight of one pharmaceuticallyacceptable antioxidant, e.g., edetate disodium, is present in thedesloratadine immediate release layer.

In other preferred embodiments, about 5.0 mg of desloratadine is presentin the immediate release layer, and 120 mg of the nasal decongestant,pseudoephedrine sulfate, is present in the sustained release layer (seeExamples 4, 5 & 6). In one preferred embodiment, the dibasic phosphatesalt preferably dibasic calcium phosphate dihydrate is present in thedesloratadine immediate release layer and no pharmaceutically acceptableantioxidant is present in either layer (see Example 4). In anotherpreferred embodiment, 5.0 mg of desloratadine and about 0.1 to about 10%of at least one antioxidant is present in the desloratadine immediaterelease layer, preferably about 4% to about 6% of a mixture of twoantioxidants, e.g., edetate disodium and citric acid, in a ratio of 5:1to 1:1, preferably in a ratio of 5:1, and about 0.1% to about 10%preferably about 0.1% to about 5%, more preferably about 0.1% to about3%, most more preferably about 1.0% of an antioxidant, e.g., edetatedisodium, is present in the PES sustained release layer (see Examples5&6).

The desloratadine was found to have an acceptable immediate releaseprofile from the immediate release layer (80% release in 0.1N HCl inless than about 45 min.) and contain less than about 2% of desloratadinedegradation products even after storage for at least 18 months at 25° C.and about 60% relative humidity (“RH”).

In another preferred embodiment, the present invention also provides asolid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid compositions. See Example 9. Inanother preferred embodiment, the present invention also provides asolid composition comprising 5.0 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid composition. See for example,Example 10. The desloratadine protective amount of a pharmaceuticallyacceptable antioxidant in the 5.0 mg and 2.5 mg solid compositions is inthe range of about 0.1% to about 10% by weight, preferably about 1% to8% or about 1% to about 6%, more preferably about 3% to about 8%, orabout 4% to about 6%, or most preferably about 5%. In a preferredembodiment of this invention, two antioxidants are present in the 5.0 mgand 2.5 mg solid compositions; one antioxidant, e.g., edeate disodium,in an amount of about 1% to about 8%, preferably about 3% to about 8%,more preferably about 4% to about 6%, or most preferably about 5%, andthe second antioxidant, e.g., citric acid, is present in an amount ofabout 1% to about 8%, preferably about 3% to about 8%, more preferablyabout 4% to about 6%, or most preferably about 5%. In another preferredembodiment, about 6% by weight of a mixture of two pharmaceuticallyacceptable antioxidants, e.g., edetate disodium and citric acid, arepresent in the 5.0 mg and 2.5 mg solid compositions in a ratio of about5:1 to about 1:5, preferably about 1:1. It has been surprisingly foundthat stearic acid could be used in place of talc to overcome a toolingproblem in the 5.0 mg and 2.5 mg solid compositions containing twopharmaceutically acceptable antioxidants, e.g., edetate disodium andcitric acid, without adversely affecting the total amount ofdesloratadine decomposition products.

We have found that the total amount of desloratadine decompositionproducts in the 5.0 mg and 2.5 mg solid compositions containing twopharmaceutically acceptable antioxidants, e.g., edetate disodium andcitric acid, is less than about 2.0%, and preferably about 1.5% byweight or less after storage at 25 c and 60% RH for extended timeperiods of at least 12 up to 15 months. In addition, at least about 80%of the desloratadine in the 5.0 mg and 2.5 mg solid compositionscontaining two pharmaceutically acceptable antioxidants, e.g., edetatedisodium and citric acid, dissolves in 0.1N HCl at 37° C. in about 45minutes.

In another preferred embodiment, a desloratadine-protective amount of apharmaceutically acceptable anti-oxidant should be present in at leastone of the bilayers, preferably one of said antioxidant in each layer.

The two layers of the bilayer tablets of this invention may be inintimate contact with one another, or have a layer at the interfaces ofthe two layers. The layer at the interfaces of the two layers may be awater-swellable film-forming polymer containing one or morepharmaceutically acceptable excipients or the layer may also contain atleast one pharmaceutically acceptable antioxidant.

The term “in intimate contact” as used herein in reference to the twolayers forming the bilayer tablet means that there is with no filminterface between the two layers.

The term “water-swellable film-forming neutral or cationic copolymericester,” as used herein means neutral and cationic copolymers of ethylacrylate and substituted unsubstituted methyl or ethyl methacrylateesters.

Typically suitable water swellable film-forming neutral copolymericesters include neutral copolymers of ethyl acrylate and methylmetharylate such as are available from Pharma Poloymers, a company ofthe Hüls Group under the EUDRAGIT® Tradename; EUDRAGIT NE30D. andKollicoat available from BASF, Mt Olive, N.J. An aqueous dispersioncontaining 30% by weight of a neutral copolymer based on ethyl crylateand methyl methoacrylate (average molecular weight of approximately800,000) is preferred.

Typically suitable water-swellable film-forming cationic co-polymericesters include cationic co-polymerers based ondimethylaminoethylmethacrylate and a neutral methacrylic ester such asthe EUDRAGIT E copolymers available from Pharma Polymers as a 12.5%solution (EUDRAGIT E 12.5) or as solid (EUDRAGIT E 100) and quaternayammonium copolymers described in USP/NF as “Amononio methacrylatecopolymer, Type A” and Type “B”. Such copolymers are available asaqueous dispersions of copolymers of acrylic and methacrylic acid esterswith a low (substitution) content of quaternary ammonium groups presentas salts, (e.g., quaternary ammonium chlorides). Type A and Type B areavailable as 30% aqueous dispersions under the EUDRAGIT RL 30D andEUDRAGIT RS 30D tradenames, respectively. Use of the water-swellablefilm—from neutral co-polymeric esters based on ethyl acrylate andmethacrylate is preferred.

The term “water soluble film modifier” as used herein means afilm-forming agent which modifies the water-swellable characteristics ofthe film-forming neutral or cationic copolymeric esters useful in thelayer at the interface of the bilayer compositions of the presentinvention. A typically suitable water soluble film-modifying agent is alow viscosity (≦20 cps) cellulose such as low viscosity hydroxypropylmethyl cellulose, low viscosity hydroxylethyl methyl cellulose; lowviscosity sodium carboxymethyl cellulose or a polyethylene glycolselected from polyethylene glycol 200 to polyethylene glycol 8000.

Use of a polyethylene glycol 6000 to polyethylene glycol 8000 as a filmmodifier is preferred.

The phrase “allergic and inflammatory conditions of the skin and airwaypassages” means those allergic and inflammatory conditions and symptomsfound on the skin and in the upper and lower airway passages from thenose to the lungs. Typical allergic and inflammatory conditions of theskin and upper and lower airway passages include seasonal and perennialallergic rhinitis, non-allergic rhinitis, asthma including allergic andnon-allergic asthma, sinusitis, colds (in combination with a NSAID,e.g., aspirin ibuprofen or APAP) and/or a decongestant e.g.pseudoephedrine), dermatitis, especially allergic and atopic dermatitis,and urticaria and symptomatic dermographism as well as retinophathy, andsmall vessel diseases, associated with diabetes mellitus.

The amount of desloratadine effective for treating or preventingallergic and inflammatory conditions of the skin and upper and lowerairway passages will vary with the age, sex, body weight and severity ofthe allergic and inflammatory condition of the patient. Typically, theamount of desloratadine effective for treating or preventing suchallergic and inflammatory conditions is in the range of about 2.5 mg/dayto about 60 mg/day, preferably about 2.5 mg/day to about 20 mg/day, orabout 4.0 mg/day to about 15 mg/day, or about 5.0 mg/day to about 10mg/day, more preferably about 5.0 mg/day to about 10.0 mg/day, and mostpreferably about 5.0 mg/day in one dose or in two divided doses of 2.5mg/dose.

Desloratadine is a non-sedating long acting histamine antagonist withpotent selective peripheral H1-receptor antagonist activity. Followingoral administration, loratadine is rapidly metabolized todescarboethoxyloratadie or desloratadine, a pharmacologically activemetabolite. In vitro and in vivo animal pharmacology studies have beenconducted to assess various pharmacodynamic effects of desloratadine andloratadine. In assessing antihistamine activity in mice (comparison ofED₅₀ value), desloratadine was relatively free of producing alterationsin behavior alterations in behavior, neurologic or autonomic function.The potential for desloratadine or loratadine to occupy brainH1-receptors was assessed in guinea pigs following i.p. administrationand results suggest poor access to central histamine receptors fordesloratadine or loratadine.

In addition to antihistaminic activity, desloratadine has demonstratedanti-allergic and anti-inflammatory activity from numerous in vitro andin vivo tests. These in vitro tests (mainly conducted on cells of humanorigin) have shown that desloratadine can inhibit many events in thecascade of allergic inflammation. These anti-inflammatory effects fordesloratadine are independent of the H1-antagonist effect ofdesloratadine and include:

-   -   The release of inflammatory mediators histamine, truptase,        leukotriene and prostaglandin D2 from mast cells;    -   The release of inflammatory cytokines including IL-4, IL-6, IL-8        and IL-13;    -   The release of the inflammatory chemokines such as RANTES        (regulated upon activation, normal T cell expressed and        presumably secreted);    -   Superoxide anion production of polymorphonuclear-neutrophils;    -   The expression of cell adhesion molecules such as intracellular        adhesion molecules (ICAM-1) and P-selection in endothelial        cells; and    -   Eosinophil migration and adhesion        In vivo studies also suggest that an inhibitory effect of        desloratadine on allergic bronchospasm and cough can also be        expected.

The clinical efficacy and safety of desloratadine has been documented inover 3,200 seasonal allergic rhinitis patients in 4 double-blind,randomized clinical trials. The results of these chemical studiesdemonstrated the efficacy of desloratadine in the treatment of adult andadolescent patients with seasonal rhinitis.

The nasal decongestants useful in the present invention includephenylpropanolamine, phenylephrine and pseudoephedrine. Pseudoephedrineas well as pharmaceutically acceptable acid additional salts, e.g.,those of HCl or H₂SO₄, is a sympathomimetic drug recognized by thoseskilled in the art as a safe therapeutic agent effective for treatingnasal congestion and is commonly administered orally and concomitantlywith an antihistamine for treatment of nasal congestion associated withallergic rhinitis. The use of pseudoephedrine as a nasal decongestant inthe present invention is preferred; the use of about 120 mgpseudoephedrine sulfate in the extended release layer is more preferred.However, lesser amounts of pseudoephedrine sulfate may be used incombination with desloratadine, e.g., in combination with the 2.5 and5.0 solid compositions of the present invention such as described inExamples 9 and 10.

In the course of development of the compressed bilayer oral dosagecomposition of this invention, it was discovered that the selection ofthe polymers for the extended release layer was critical to achieve thedesired extended release period of at least 12 hours, forpseudoephedrine sulfate. For example, the use of hydroxypropylmethylcellulose 4,000 cps or 15,000 cps as polymers in the matrix coredid not provide this more preferred extended release period of at least16 hours for dose of pseudoephedrine sulfate. We discovered that only byselecting for inclusion into the matrix core of specific weight ratiosof three specific polymers was the desired pseudoephedrine releaseprofile achieved. Only by combining (1) about one part by weight,preferably 1.05 parts by weight of hydroxypropyl methylcellulose 2208USP, 100,000 cps with (2) about one part by weight, preferably 1.0 partsby weight of microcrystalline cyellulose together with (3) about0.15-0.20 part by weight, preferably 0.17-0.18 parts by weight ofpovidone (per 1.05 parts by weight of hydroxypropyl methylcellulose) asa secondary binder was the more preferred extended release profile of atleast 12 hours for pseudoephedrine sulfate from the extended releaselayer. The extended release layer also contains specific amounts ofsilicon dioxide as a glidant and magnesium stearate as a lubricant. Thetablet hardness 20±4 Strong-Cobb Units (SCU) is not greatly affected bythe higher level of lubricant (6 mg/tablet) but it is preferred tomaintain the lubricant level at 1/9 part by weight of lubricant to onepart by weight of povidone as secondary binder.

The term “lubricant’ as used herein refers to a substance added to thedosage form to enable the dosage form, e.g., a tablet, after it has beencompressed to release from the mold or die.

Suitable lubricants include talc, magnesium stearate, calcium stearate,stearic acid, hydrogenated vegetable oils and the like. Preferably,magnesium stearate or talc is used.

The term “glidants” as used herein refers to a substance, such as ananti-caking agent, which improves the flow characteristics of a powdermixture.

Suitable glidants include silicon dioxide and talc. Preferably, silicondioxide is used.

The term “binders” as used herein means any material that is added topharmaceutical compositions to help hold such compositions together andrelease the medicament therefrom.

Suitable binders are selected those found in NF XVIII, page 2206 (1995)and include povidones, starches, celluloses, alginates, and gums and lowmolecular weight hydroxypropyl melthyl celluloses, especiallyhydroypropyl methyl celluose 2910.

The term “pharmaceutically acceptable water insoluble basic calcium,magnesium and aluminium salts” as used herein means the pharmaceuticallyacceptable carbonates, phosphates, silicates and sulfates of calcium,magnesium and aluminum or mixtures thereof. Typically suitablepharmaceutically acceptable basic salts include calcium sulfateanhydrous, hydrates of calcium sulfate, such as calcium sulfatedihydrate, magnesium sulfate anhydrous, hydrates of magnesium sulfate,dibasic calcium phosphate, dibasic calcium silicate, magnesiumtrisilicate, magnesium phosphate, aluminum silicate, and hydrates ofmagnesium phosphate, aluminum phosphate; and calcium phosphate is morepreferred. The use of dibasic calcium phosphate dihydrate is mostpreferred.

The desloratadine-protective amount of a pharmaceutically acceptablewater insoluble basic calcium, magnesium or aluminum salt is in therange of about 50-60% of the DL immediate release layer, and the w/wratio of the pharmaceutically acceptable water insoluble basic calcium,magnesium or aluminum salt to DL is in the range of about 8:1 to about40:1, more preferably is in the range of about 10:1 to about 20:1, andmost preferably is in the range of about 10:1 to about 11:1.

In the preferred embodiment of the present invention wherein adesloratadine protective amount of a pharmaceutically acceptableantioxidant is present, the water insoluble basic calcium salt is notpresent in the immediate release layer containing desloratadine; in itsplace, at least one, preferably two pharmaceutically acceptableantioxidants are present, e.g., edetate sodium and citric acid and theamount of microcrystalline cellulose is increased. In addition, when thepharmaceutically acceptable antioxidant is used in place of the waterinsoluble basic calcium, magnesium or aluminum salt, the povidone in thesustained release layer is replaced by another binder, preferably a lowmolecular weight hydroxypropyl methyl cellulose (“HPMC”), preferablyHPMC 2910.

In the preparation of the bilayer tablet, the sustained release layer iscompacted first. The immediate release second layer is added on top anda compression force sufficient to form a bilayer tablet is applied inthe range of 8-12 kilo Newtons, preferably about 9 kilo Newtons (kN).

The dried sustained release granulation is milled and blended withrequisite amounts of silicon dioxide and magnesium stearate. In apreferred embodiment, a pharmaceutically acceptable blue dye containingEDTA as a chelating agent is incorporated into the immediate releasedesloratadine layer. Use of a pharmaceutically acceptable blue dye, e.g.FD& C blue dye No. 2 Aluminum Lake 5627 is preferred.

Example 1

This example illustrates preparation of the preferred oral dosagecomposition of this invention. The ingredients and specific amountsthereof are listed below.

A. Method of Manufacture of the Immediate Release Layer

-   -   1. Prepare starch paste by dispersing the paste portion of corn        starch into purified water in a suitable container equipped with        an agitator.    -   2. While mixing, heat the contents to approximately 95° C. and        maintain the temperature for approximately 30 minutes.    -   3. After Step 2 is completed, add an additional purified water        and allow the starch paste to cool to approximately 50° C.    -   4. While mixing, add desloratadine to the starch paste. Continue        mixing during the granulation step.    -   5. Pass the FD&C blue No. 2 aluminum lake containing EDTA as a        chelating, e.g., Spectra Spray Med Blue, with the required        amount of dibasic calcium phosphate through a suitable sieve or        mill.    -   6. Charge to a suitable fluid bed processing bowl the remaining        dibasic calcium phosphate dihydrate, the milled material from        Step 5, a portion of the corn starch, and a portion of        microcrystalline cellulose. Place the processing bowl into the        fluid bed processor.    -   7. Fluidize the powder bed until the product temperature reaches        approximately 29° C.    -   8. Begin granulating the powder by pumping the starch paste from        Step 4 into the fluidized bed at a suitable spray rate and a bed        temperature of approximately 22° C.    -   9. Continue to dry the granulation at an inlet air temperature        of approximately 60° C. until a final loss on drying (LOD) of 2%        or less is achieved.    -   10. Pass the dried granulation through a suitable sieve or mill.    -   11. Charge the granulation to a suitable blender and add the        requisite amounts of the remaining portion of microcrystalline        cellulose, corn starch, and talc. Blend for 5 minutes.

B. Manufacture of Sustained Release Mix:

-   -   1. Charge purified water and alcohol to a suitable container        equipped with an agitator.    -   2. Dissolve povidone in the water/alcohol mixture. Continue        mixing for a minimum of 10 minutes.    -   3. Mix hydroxypropyl methylcellulose, pseudoephedrine sulfate        and microcrystalline cellulose in a suitable granulator.    -   4. Granulate the mix with the povidone solution, using        additional water/alcohol mixture if necessary to achieve the        appropriate granulation consistency.    -   5. Dry the wet granulation at approximately 50° C. in a suitable        dryer until the loss on drying (LOD) is between 1% and 3%.    -   6. Pass the dried granulation through a suitable sieve or mill.    -   7. Charge the milled granulation to a suitable blender.    -   8. Pass the silicon dioxide through a No. 30 mesh screen into        the blender.    -   9. Blend the requisite amount of screened silicon dioxide with        the granulation for approximately 10 minutes in a suitable        blender.    -   10. Pass the magnesium stearate through a No. 30 mesh screen.    -   11. Blend the requisite amount of screened magnesium stearate        with the mix from Step 9 for 5 minutes.

C. Compression:

-   -   Compress the two blends to specifications as bilayer tablets        using a suitable double-layer tablet press using a compression        force of 9 k Newtons. Compress the sustained release layer        first.    -   Tablet Weight: 450 mg±5%        -   Sustained release layer: 350 mg±5%        -   Immediate release layer 100 mg±5%    -   Hardness: 20±4 SCU (Strong Cobb units)    -   The following bilayer tablet was prepared using the above        procedure.

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn StarchNF/Ph. Eur. 11.0 Dibasic Calcium Phosphate Dihydrate USP/Ph. Eur. 53.0Microcrystalline Cellulose NF/Ph. Eur./JP 30.22 Talc USP/Ph. Eur. 3.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.28 Water Purified USP/Ph. Eur.— TOTAL 100.00and

Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, USP, 105.0 100,000 cps (K100M)/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 100.0 Povidone USP/Ph.Eur./JP 18.0 Silicon Dioxide NF 5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine) 2.0 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol— TOTAL 350.0 TOTAL TABLET 450.0

Hardness: 20±4 SCU (Strong Cobb units)

Example 2

The procedure of Example 1 was used; edetate disodium was used in placeof the dibasic calcium salt and the amount of microcrystalline cellulosein the DL layer was increased. Edetate disodium was used in thesustained release layer and hydroxypropyl methylcellulose 2910 was usedin place of povidone.

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn StarchNF/Ph. Eur. 8.0 Microcrystalline Cellulose NF/Ph. Eur./JP 71.35 EdetateDisodium 5.0 Talc USP/Ph. Eur. 3.0 Dye FD&C Blue No. 2 Aluminium Lake5627 0.15 Water Purified USP/Ph. Eur. — TOTAL 100.00and

Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, USP/Ph. Eur. 105.0 MicrocrystallineCellulose NF/Ph. Eur./JP 103.5 Edetate Disodium 3.5 HydroxypropylMethylcellulose 2910 USP/Ph. Eur./JP 10.5 Silicon Dioxide NF 5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph.Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL TABLET 450.0

Hardness: 20±4 SCU (Strong Cobb units)

Example 3

The procedure of Example 2 was used, but 1 mg of citric acid was addedto the DL layer and the amount of microcrystalline cellulose wasdecreased by 1 mg.

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn StarchNF/Ph. Eur. 18.0 Edetate Disodium 5.0 Citric Acid 1.0 MicrocrystallineCellulose NF/Ph. Eur./JP 70.35 Talc USP/Ph. Eur. 3.0 Dye FD&C Blue No. 2Aluminium Lake 5627 0.15 Water Purified USP/Ph. Eur. — TOTAL 100.00And Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 100,000 cps 105.0 (K100M)USP/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 Edetate Disodium3.5 Hydroxypropyl Methylcellulose 2910 10.5 Silicon Dioxide NF 5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph.Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL TABLET 450.0

Hardness: 20±4 SCU (Strong Cobb units)

Example 4

The procedure of Example 1 was used. The bilayer tablet of Example 1 wasmodified by including 5.0 mg of desloratadine in the immediate releaselayer—(a 24 hour dose)—with the appropriate changes in amounts of theother ingredients and using the 12-hr dose pseudoephedrine sustainedrelease layer of Example 1. Hardness: 20±4 SCU (Strong Cobb units)

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 5.0 Corn StarchNF/Ph. Eur. 11.0 Dibasic Calcium Phosphate Dihydrate USP/Ph. Eur. 53.0Microcrystalline Cellulose NF/Ph. Eur./JP 27.72 Talc USP/Ph. Eur. 3.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.28 Water Purified USP/Ph. Eur.— TOTAL 100.00and

Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 (K100M)USP/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 100.0 Povidone USP/Ph.Eur./JP 18.0 Silicon Dioxide NF 5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine) 2.0 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol— TOTAL 350.0 TOTAL TABLET 450.0

Example 5

The procedure of Example 1 was used and the bilayer tablet of Example 4was modified by replacing the dibasic calcium phosphate dihydrate in theimmediate release layer with 10 mg of edetate disodium and increasingthe amount of microcrystalline cellulose by 2.7 mg. Hardness: 20±4 SCU(Strong Cobb units)

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 5.0 Corn StarchNF/Ph. Eur. 36.0 Microcrystalline Cellulose NF/Ph. Eur./JP 142.7 EdetateDisodium 10.0 Talc USP/Ph. Eur. 6.0 Dye FD&C Blue No. 2 Aluminium Lake5627 0.30 Water Purified USP/Ph. Eur. — TOTAL 200.00and

Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph. Eur.Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 HydroxypropylMethylcellulose 2910 10.5 Edetate Disodium 3.5 Silicon Dioxide NF 5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph.Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL Tablet Weight 550.0

Example 6

The bilayer tablet of Example 5 was modified by adding 2.0 mg of citricacid to the immediate release layer and decreasing the amount ofmicrocrystalline cellulose by 2.7 mg and using the pseudoephedrinesustained release layer of Example 1. Hardness: 20±4 SCU (Strong Cobbunits)

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 5.0 Corn StarchNF/Ph. Eur. 36.0 Microcrystalline Cellulose NF/Ph. Eur./JP 140.7 EdetateDisodium 10.0 Citric Acid 2.0 Talc USP/Ph. Eur. 6.0 Dye FD&C Blue No. 2Aluminium Lake 5627 0.30 Water Purified USP/Ph. Eur. — TOTAL 200.00And Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph. Eur.Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 HydroxypropylMethylcellulose 2910 10.5 Edetate Disodium 3.5 Silicon Dioxide NF 5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph.Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL Tablet Weight 550.0

Example 7

The bilayer tablet of Example 5 was modified by replacing the talc withan equivalent weight of stearic acid, and by adding an additional 8.0 mgof citric acid to the immediate release layer and decreasing the amountof microcrystalline cellulose by 8.0 mg and replacing 4.0 g of themicrocrystalline cellulose and all of the hydroxypropyl methylcelluloseand edetate disodium with 18.0 g of popovidone the pseudoephedrine inthe sustained release layer of Example 6.

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 5.0 Corn StarchNF/Ph. Eur. 36.0 Microcrystalline Cellulose NF/Ph. Eur./JP 132.7 EdetateDisodium USP 10.0 Citric Acid Anhydrous, USP 10.0 Stearic Acid, NF. 6.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.30 Water Purified USP/Ph. Eur.— TOTAL 200.00And Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph.Eur(K100M). Microcrystalline Cellulose NF/Ph. Eur./JP 99.5 Povidone, USP18.0 Silicon Dioxide NF 5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine) 2.5 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol— TOTAL 350.0 TOTAL Tablet Weight 550.0

Example 8

The bilayer tablet of Example 7 was modified by decreasing the weight ofall ingredients in the desloratadine immediate release layer by 50% andusing the sustained release layer of Example 7

Desloratadine Immediate Release Layer:

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn StarchNF/Ph. Eur. 18.0 Microcrystalline Cellulose NF/Ph. Eur./JP 66.35 EdetateDisodium USP 5.0 Citric Acid Anhydrous, USP 5.0 Stearic Acid, NF. 3.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.15 Water Purified USP/Ph. Eur.— TOTAL 100.00And Pseudoephedrine Sulfate Sustained Release Layer

INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph.Eur(K100M). Microcrystalline Cellulose NF/Ph. Eur./JP 99.5 Povidone, USP18.0 Silicon Dioxide NF 5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine) 2.5 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol— TOTAL 350.0 TOTAL Tablet Weight 450.0

Example 9

A desloratadine (2.5 mg) tablet was prepared by using the desloratadineimmediate release layer of Example 8.

INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn StarchNF/Ph. Eur. 18.0 Microcrystalline Cellulose NF/Ph. Eur./JP 66.35 EdetateDisodium USP 5.0 Citric Acid Anhydrous, USP 5.0 Stearic Acid, NF. 3.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.15 Water Purified USP/Ph. Eur.— TOTAL Tablet Weight 100.00

Example 10

A desloratadine (5.0 mg) tablet was prepared by using the desloratadineimmediate release layer of Example 7.

INGREDIENT mg/composition Desloratadine, micronized 5.0 Corn StarchNF/Ph. Eur. 36.0 Microcrystalline Cellulose NF/Ph. Eur./JP 132.7 EdetateDisodium USP 10.0 Citric Acid Anhydrous, USP 10.0 Stearic Acid, NF. 6.0Dye FD&C Blue No. 2 Aluminium Lake 5627 0.30 Water Purified USP/Ph. Eur.— TOTAL TABLET WEIGHT 200.00

The in vitro dissolution profile of the tablets of Examples 1-10 weremeasured in a stirred 0.1N HCl solution at 37° C. (1^(st) hour) andthereafter in a stirred phosphate buffer having a pH of 7.5 at 37° C.The 80% of desloratadine in the immediate release layers was dissolvedwithin the first 30 minutes and the total dose of pseudoephedrinesulfate in the sustained release layers of Examples 1-8 was slowlyreleased via erosion and dissolution mechanisms over a period of atleast 12 hours. (with 30-45% in 1 hr, 50-605% in 2 hrs. and ≧80% in 6hrs).

Similar results would be expected if a decongestant effective amount ofanother pharmaceutically acceptable pseudoephedrine salt, e.g.,pseudoephedrine hydrochloride was used in place of pseudoephedrinesulfate.

The compositions of the present invention are useful for treatment ofallergic and/or inflammatory conditions of the skin (e.g. urticaria) andthe upper and lower airway passages including the nasal and non-nasalsymptoms of perennial and seasonal allergic rhinitis including nasalcongestion in a patient in need of such treating. The precise dosage anddosage regimen may be varied by the attending clinician in view of theteachings herein depending upon the requirements of the patient, e.g.,the patients age, sex and the severity of the allergic and/orinflammatory condition being treated. Determination of the proper dosageand dosage regimen for a particular patient will be within the skill ofthe attending clinician. While we have hereinabove presented a number ofpreferred embodiments of this invention by way of example, it isapparent that the scope of the invention is to be defined by the scopeof the appended claims.

1. A solid composition comprising: (1) an immediate release layercomprising an anti-allergic effective amount of desloratadine and adesloratadine-protective amount of two pharmaceutically acceptableantioxidants; and (2) a sustained release layer comprising an effectiveamount of pseudoephedrine or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable sustained release agent; wherein thetotal amount of desloratadine degradation products in the solidcomposition is less than or equal to about 2% by weight, and wherein atleast about 80% of the desloratadine dissolves in a 0.1N HCl solution at37° C. in about 45 minutes.
 2. The solid composition of claim 1 whereinthe two pharmaceutically acceptable antioxidants are edetate disodiumand citric acid.
 3. A solid composition comprising: (1) an immediaterelease first layer comprising an anti-allergic effective amount ofdesloratadine and at least one pharmaceutically acceptable antioxidant;and (2) a sustained release second layer comprising an effective amountof pseudoephedrine or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable sustained release agent; wherein the totalamount of desloratadine degradation products in the solid composition isless than or equal to about 2% by weight, and wherein at least about 80%of the desloratadine dissolves in a 0.1N HCl solution at 37° C. in about45 minutes.
 4. A solid composition comprising: (1) an immediate releasefirst layer comprising about 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant; (2) a sustained release second layer comprisingabout 120 mg of pseudoephedrine or a pharmaceutically acceptable saltthereof; and (3) a pharmaceutically acceptable excipient, wherein atleast about 80% of the desloratadine dissolves in a 0.1N HCl solution at37° C. in about 45 minutes.
 5. The solid composition of claim 4 whereinthe total amount of desloratadine degradation products is less than orequal to about 2% by weight.
 6. The solid composition of claim 4 whereina desloratadine-protective amount of a pharmaceutically acceptablebinder is present in the sustained release second layer.
 7. The solidcomposition comprising a first and a second layer wherein the firstlayer is an immediate release layer comprising: INGREDIENTmg/composition Desloratadine, micronized 5.0 Corn Starch 36.0Microcrystalline Cellulose 140.7 Edetate Disodium 10.0 Citric Acid 2.0Talc 6.0 Dye 0.30 TOTAL 200.00

and wherein the second layer is a sustained release layer comprising:INGREDIENT mg/composition Pseudoephedrine Sulfate 120.0 HydroxypropylMethylcellulose 2208, 100,000 cps 105.0 Microcrystalline Cellulose 103.5Hydroxypropyl Methylcellulose 2910 10.5 Edetate Disodium 3.5 SiliconDioxide 5.0 Magnesium Stearate (Non-Bovine) 2.5 TOTAL 350.0 TOTAL TabletWeight 550.0

wherein the total amount of desloratadine degradation products in thesolid composition is less than or equal to about 2% by weight.
 8. Asolid composition comprising a first layer and a second layer, whereinthe first layer is an immediate release first layer comprising:INGREDIENT mg/composition Desloratadine, micronized 2.5 Corn Starch 18.0Microcrystalline Cellulose 71.22 Edetate Disodium 5.0 Citric Acid 1.0Talc 3.0 Dye 0.28 TOTAL 100.00

and wherein the second layer is a sustained release layer comprising:INGREDIENT mg/composition Pseudoephedrine Sulfate 120.0 HydroxypropylMethylcellulose 2208 105.0 Microcrystalline cellulose 103.5 EdetateDisodium 3.5 Hydroxypropyl Methylcellulose 2910 10.5 Silicon Dioxide 5.0Magnesium stearate 2.5 TOTAL 350.0

and wherein total amount of desloratadine degradation products in thesolid composition is less than or equal to about 2% by weight.
 9. Thesolid composition of claim 8 wherein at least about 80% of thedesloratadine dissolves in a 0.1N HCl solution at 37° C. in about 45minutes.
 10. A method of treating allergic or inflammatory conditions ofthe upper and lower airway passages and skin which comprisesadministering to a patient in need of such treating an effective amountof the solid composition of claim
 1. 11. A method of treating the signsand symptoms of nasal congestion associated with allergic andinflammatory conditions of the upper or lower airway passages and skinwhich comprises administering to a patient in need of such treating aneffective amount of the solid composition of claim
 1. 12. A method oftreating the signs and symptoms of nasal congestion associated withallergic or inflammatory conditions of the upper and lower airwaypassages and skin which comprises administering to a patient in need ofsuch treating an effective amount of the solid composition of claim 3.13. A method of treating the signs and symptoms of nasal congestionassociated with allergic or inflammatory conditions of the upper andlower airway passages and skin which comprises administering to apatient in need of such treating an effective amount of the solidcomposition of claim
 4. 14. A method of treating the signs and symptomsof nasal congestion associated with allergic or inflammatory conditionsof the upper and lower airway passages and skin which comprisesadministering to a patient in need of such treating an effective amountof the solid composition of claim
 8. 15. A method of treating the signsand symptoms of urticaria which comprises administering to a patient inneed of such treating an effective amount of the solid composition ofclaim
 1. 16. A method of treating the signs and symptoms of urticariawhich comprises administering to a patient in need of such treating aneffective amount of the solid composition of claim
 3. 17. A method oftreating the signs and symptoms of urticaria which comprisesadministering to a patient in need of such treating an effective amountof the solid composition of claim
 4. 18. A method of treating the signsand symptoms of urticaria which comprises administering to a patient inneed of such treating an effective amount of the solid composition ofclaim
 7. 19. A method of treating the signs and symptoms of urticariawhich comprises administering to a patient in need of such treating aneffective amount of the solid composition of claim
 8. 20. A method oftreating the nasal and non-nasal symptoms of perennial or seasonalallergic rhinitis which comprises administering to a patient in need ofsuch treating an effective amount of the solid composition of claim 1.21. A method of treating the nasal and non-nasal symptoms of perennialor seasonal allergic rhinitis which comprises administering to a patientin need of such treating an effective amount of the solid composition ofclaim
 3. 22. A method of treating the nasal and non-nasal symptoms ofperennial or seasonal allergic rhinitis which comprises administering toa patient in need of such treating an effective amount of the solidcomposition of claim
 4. 23. A method of treating the nasal and non-nasalsymptoms of perennial or seasonal allergic rhinitis which comprisesadministering to a patient in need of such treating an effective amountof the solid composition of claim
 7. 24. A method of treating the nasaland non-nasal symptoms of perennial or seasonal allergic rhinitis whichcomprises administering to a patient in need of such treating aneffective amount of the solid composition of claim
 8. 25. A method oftreating allergic or inflammatory conditions of the upper and lowerairway passages and skin which comprises administering to a patient inneed of such treating an effective amount of the solid composition ofclaim
 3. 26. A method of treating allergic or inflammatory conditions ofthe upper and lower airway passages and skin which comprisesadministering to a patient in need of such treating an effective amountof the solid composition of claim
 4. 27. A method of treating allergicor inflammatory conditions of the upper and lower airway passages andskin which comprises administering to a patient in need of such treatingan effective amount of the solid composition of claim
 7. 28. A method oftreating allergic or inflammatory conditions of the upper and lowerairway passages and skin which comprises administering to a patient inneed of such treating an effective amount of the solid composition ofclaim
 8. 29. A method of treating the signs and symptoms of nasalcongestion associated with allergic and inflammatory conditions of theupper or lower airway passages and skin which comprises administering toa patient in need of such treating an effective amount of the solidcomposition of claim 7.